Acetaminophen with Codeine Phosphate (Tylenol® with Codeine) or Hydrocodone Bitartrate (Vicodin®) or Oxycodone (Tylox®) is commonly used analgesic drugs, indicated for the relief of moderate to moderately severe pain. Acetaminophen with Codeine or Hydrocodone combines the analgesic effects of a centrally acting analgesic, codeine or hydrocodone, with a peripherally analgesic, acetaminophen. Opioids have for many years been used as analgesics to treat severe pain. They, however, produce undesirable side effects and as a result cannot be given repeatedly or at high doses. The side effect problems are well documented in the literature (J. Jaffe and W. Martin in chapter 15, “The Pharmacological Basis of Therapeutics”, editors L. Goodman and A. Gilman, 5th Edition, 245, 1975), which discloses that morphine and its congeners, e.g., codeine, hydrocodone and oxycodone, are opioid agonist analgesics that exhibit side effects such as respiratory depression, constipation, tolerance and abuse liability.
As alternatives to using opioids, non-opioids such as acetaminophen (APAP) and aspirin are used as analgesics. APAP, like aspirin, is not subject to the tolerance, addiction and toxicity of the opioid analgesics. However, APAP and aspirin are only useful in relieving pain of moderate intensity, whereas the opioid analgesics are useful in relieving more intense pain; See Woodbury, D. and Fingl, E. in “The Pharmacological Basis of Therapeutics”, 5th Ed.; Goodman, L. and Gilman, A., Chapter 15, pages 325 (1975).
To reduce the side effect problems of opioids, opioids have been combined with other drugs including non-opioid analgesic agents, which lowers the amount of opioid needed to produce an equivalent degree of analgesia. It has been claimed that some of these combination products also have the advantage of producing a synergistic analgesic effect. For example, A. Takemori, Annals New York Acad. Sci., 281, 262 (1976) discloses that compositions including combinations of opioid analgesics with drugs other than analgesics exhibit a variety of effects, i.e., subadditive (inhibitory), additive or superadditive. R. Taber et al., J. Pharm. Expt. Thera., 169(1), 29 (1969) disclose that the combination of morphine and methadone, another opioid analgesic, exhibits an additive effect. U.S. Pat. No. 4,571,400 discloses that the combination of dihydrocodeine, an opioid analgesic, and ibuprofen, a non-opioid analgesic, provides superadditive effects when the components are within certain ratios. A. Pircio et al., Arch. Int. Pharmacodyn., 235, 116 (1978) report superadditive analgesia with a 1:125 mixture of butorphanol, another opioid analgesic, and acetaminophen (APAP), a non-opioid analgesic, whereas a 1:10 mixture did not show any statistically significant superadditive analgesia.
An immediate-release tablet composition comprising a tramadol material and acetaminophen, and its use, was invented (U.S. Pat. No. 5,336,691). The usual adult dosage is one or two tablets (Ultracet™) every four to six hours. The compositions are pharmacologically useful in treating pain and tussive conditions. The compositions are also subject to less opioid side-effects such as abuse liability, tolerance, constipation and respiratory depression.
The benefits of sustained release dosage forms are well documented. To reduce the dose segment and increase the patient compliance is one of the purposes with sustained release formulations. It has been reported that sustained release oral solid dosage forms of opioid analgesics are provided as multiparticulate systems which are bioavailable and which provide effective blood levels of the opioid analgesic for at least about 24 hours (see U.S. Pat. No. 6,294,195). Sustained release tablets for acetaminophen may be prepared using coated acetaminophen particles and uncoated acetaminophen particles to compress them to tablets providing a combination of immediate release and sustained release dosage forms (see U.S. Pat. No. 6,126,969). An acetaminophen-sustained release tablet or tablet layer is formed by making a wet granulation, using Povidone (PVP) in water or alcohol-water as the granulating fluid which is mixed with acetaminophen, hydroxyethyl cellulose, a wicking agent e.g. microcrystalline cellulose, then drying and milling the granulation and blending with dry powdered erosion promoter, e.g. pregelatinized starch, wicking agent, lubricant e.g. magnesium stearate and glidant e.g. silicon dioxide, and compressing the resultant granulation, which upon administration results in a slow release of the acetaminophen (see U.S. Pat. No. 4,820,522).
It has previously been known in the art that controlled release compositions of opioid analgesics such as morphine, hydromorphone or salts thereof could be prepared in a suitable matrix. For example, U.S. Pat. No. 4,990,341 (Goldie) describes hydromorphone compositions wherein the dissolution rate in vitro of the dosage form, when measured by the USP Paddle Method at 100 rpm in 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37.degree. C., is between 12.5 and 42.5% (by wt) hydromorphone released after 1 hour, between 25 and 55% (by wt) released after 2 hours, between 45 and 75% (by wt) released after 4 hours and between 55 and 85% (by wt) released after 6 hours.
In the pharmaceutical market today, there are only sustained release dosage forms available for individual analgesic drugs, for example, oxycodone or acetaminophen.